Diagnosis of depression is increasing in the United States, and women are twice as likely as men to suffer from depressive symptoms. With the advent of the selective serotonin reuptake inhibitors (SSRIs), antidepressant use has increased dramatically during the 1980s and 1990s, and the types of antidepressants prescribed have changed. Recent evidence that antidepressants can reduce the occurrence of menopausal hot flashes has led to predictions that antidepressant use may increase still further, particularly among women who are reluctant to take hormone replacement therapy due to concerns about breast cancer risk. Thus, better understanding of any possible role of antidepressants in breast cancer etiology is of substantial and growing public health importance. Initial concern about a role of antidepressants in human carcinogenesis was sparked by reports of increased occurrence of mammary tumors in rats administered tricyclic antidepressants or SSRIs. Epidemiologic findings have been inconsistent, but have not dispelled this concern. Two recent studies reported an elevated risk of breast cancer among users of some antidepressants; however, the class or type of antidepressant associated with increased risk differed. These studies were limited by the potential for error in self-reported drug use, and by relatively small numbers of exposed women. We propose to conduct a population-based, case control study to examine the association between antidepressant use and risk of breast cancer within the Group Health Cooperative of Puget Sound (GHC). Approximately 3,652 women diagnosed with first primary breast cancer (3,080 with invasive disease) during 1990-2000 and 7,304 randomly selected, matched controls will be included. Antidepressant use will be ascertained through the GHC pharmacy database, and information on potential confounding factors will be obtained from risk factor surveys routinely administered by GHC. The large study size and broad, recent interval of diagnosis years of cases will allow examination of the type, timing, and duration of use of antidepressants overall, classes of drugs (e.g., SSRIs or tricyclics), and individual drugs such as fluoxetine and paroxetine. Use of the pharmacy database will provide unbiased and complete exposure data relative to previous studies based on self-reported drug use.